P2D Bioscience is developing the selective, non-addicting dopamine transport (DAT) inhibitor, PD2XXX, for the symptomatic treatment of Alzheimer's disease (AD). The core symptom of AD is short-term memory impairment. (DSM-IV) In preliminary studies, PD2XXX improved short term memory by over 110% in a well-accepted triple transgenic mouse model of AD (3xTg-AD). 3xTg-AD mice carry mutations of the APP, tau and presenilin 1 genes. Further, 3xTg-AD mice develop the age-dependent plaques and tangles characteristic of AD. Also, 3xTg-AD mice demonstrate the age-dependent cognitive decline observed in Alzheimer's patients. Therefore, our preliminary data indicate that PD2XXX significantly improved short- term memory in an AD model that mirrors the age-dependent development of Alzheimer's neuropathology as well as the cognitive deficits that characterize Alzheimer's clinical pathology. The long term goal of the proposed studies is to develop a safe and effective treatment for AD with limited or no abuse potential. The proposed studies will determine if PD2XXX is an effective treatment for the cognitive symptoms of AD in 3xTg-AD mice: a) as a stand-alone therapy, or b) as an adjunct therapy added to the NMDA antagonist, memantine, a widely prescribed Alzheimer's treatment. Further, we will determine if PD2XXX plasma levels are correlated with improvement in cognitive performance in 3xTg-AD mice. Our proposed Specific Aims are: Specific Aim 1: Determine PD2XXX efficacy as an Alzheimer's stand-alone therapy in 3xTg-AD mice. Also, determine if PD2XXX plasma levels are correlated with clinical response in 3xTg-AD mice. Specific Aim 2: Determine PD2XXX efficacy as an Alzheimer's adjunct therapy in 3xTg-AD mice treated with the FDA-approved AD treatment, memantine. Also, determine if PD2XXX plasma levels are correlated with clinical response in 3xTg-AD mice.